Synthesis method of natural product hypermonone G
By constructing an oxabicyclic [2.2.1]heptane skeleton using a specific catalyst, the problems of long steps, high toxicity, and lack of modifiability in the synthesis of hypermonone G in the prior art are solved, and an efficient and green method for the synthesis of hypermonone G is realized.
Patent Information
- Application Number
- CN202311561188.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-22
- Publication Date
- 2026-01-27
- Estimated Expiration
- 2043-11-22
AI Technical Summary
Existing methods for synthesizing hypermonone G suffer from problems such as long steps, poor atom economy, use of toxic catalysts, the ability to synthesize only racemic mixtures, and the inability to modify the structure, making it difficult to achieve rapid, simple, and efficient artificial synthesis.
Using 3,7-dimethyloct-6-en-1-yn-3-ol as a raw material, an oxabicyclo[2.2.1]heptane skeleton was constructed through a mixed catalyst of triphenylphosphine chloride gold or methyltriphenylphosphine gold with silver tetrafluoroborate or phosphotungstic acid, and hypermonone G was obtained through stereoselective reaction. The reaction conditions were mild and the process was simple and efficient.
The asymmetric synthesis of hypermonone G was achieved. The reaction was carried out at room temperature and pressure. The catalyst was non-toxic and harmless, environmentally friendly, and highly atom-economical, making it suitable for widespread application.
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Figure CN119954758B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for synthesizing a compound, and more particularly to a method for synthesizing the natural product hypermonone G. Background Technology
[0002] Hypermonone G is a natural product of an oxygen-containing heterobicyclic [2.2.1] bridged ring skeleton isolated from St. John's wort. This natural product has a unique structure, and researchers have found that it can reverse multidrug resistance to antitumor drugs.
[0003] However, there are many compounds isolated from St. John's wort, and it is very difficult to isolate and purify the compound hypermonone G. Artificial synthesis is the most effective way to solve this problem, but there are no reports of artificial synthesis of this natural product so far.
[0004] Previous methods for synthesizing such natural product skeletons mainly include the following: 1) intramolecular SN2 substitution of hydroxymethyl-substituted epoxides; 2) radical cyclization induced by organomercury compounds; 3) Prins reaction tandem cyclization; 4) tandem reaction catalyzed by metal Lewis acids; and 5) cycloaddition reaction based on TMM, etc.
[0005] However, these synthetic methods have some drawbacks: 1) The preparation of the ring-closed precursors involves long linear steps, resulting in significant waste and low atom economy; 2) Many metal catalysts used in the past are highly toxic, posing a risk to operators; 3) They cannot be synthesized asymmetrically, and only their racemic compounds can be constructed; 4) The ring-closed structure lacks modifiable functional groups, making it impossible to couple with other parts and resulting in weak modifiability; 5) The preparation conditions for the ring-closed precursors are harsh, making preparation relatively difficult.
[0006] For the reasons mentioned above, it is undoubtedly necessary to find rapid and simple precursor molecules and synthesize them using simple, efficient, economical and highly sustainable methods. Summary of the Invention
[0007] To address the aforementioned technical problems, this invention provides a method for synthesizing the natural product hypermonone G. The method of this invention asymmetrically synthesizes the natural product hypermonone G under mild reaction conditions, and the process is simple, efficient, environmentally friendly, highly practical, and atom-economical, making it suitable for widespread application.
[0008] The technical solution of the present invention is a method for synthesizing the natural product hypermonone G, which uses 3,7-dimethyloct-6-en-1-yn-3-ol as a raw material, and constructs the oxabicyclo[2.2.1]heptane skeleton shown in compound I through the catalytic action of a catalyst. Then, the oxabicyclo[2.2.1]heptane skeleton is subjected to a stereoselective reaction to obtain the final product hypermonone G.
[0009] The chemical structural formula of compound I is as follows:
[0010] The chemical structural formula of the product hypermonone G is as follows:
[0011] Preferably, the method for synthesizing the aforementioned natural product hypermonone G includes the following steps:
[0012] S1. Dissolve the raw material 3,7-dimethyloct-6-en-1-yn-3-ol in an organic solvent to obtain solution A;
[0013] S2. Dissolve the catalyst in an organic solvent to obtain solution B;
[0014] S3. Add solution B to solution A and stir until the reaction is complete. Then add water to quench the reaction. After extraction, drying, concentration, column chromatography and concentration, the oxabicyclo[2.2.1]heptane skeleton of compound I is obtained.
[0015] S4. Dissolve the oxabicyclo[2.2.1]heptane skeleton in an organic solvent to obtain solution C;
[0016] S5. Add borane dimethyl sulfide solution to solution C, stir until the reaction is complete, then transfer the solution to an environment of -5℃ to 5℃, add sodium hydroxide solution, react for 20-40 min, add hydrogen peroxide solution, transfer to room temperature and continue the reaction for 0.5-1.5 h, after the reaction is complete, add saturated ammonium chloride to quench the reaction, and then extract, dry, concentrate, column chromatography and concentrate in sequence to obtain the product hypermonone G.
[0017] Preferably, in the aforementioned method for synthesizing the natural product hypermonone G, the catalyst is a mixture of triphenylphosphine gold chloride and silver tetrafluoroborate, a mixture of methyltriphenylphosphine gold and phosphotungstic acid, or a compound.
[0018] Preferably, in the aforementioned method for synthesizing the natural product hypermonone G, the mass ratio of triphenylphosphine chlorogold to silver tetrafluoroborate and the mass ratio of methyltriphenylphosphine gold to phosphotungstic acid are 1:1.
[0019] Preferably, in the aforementioned method for synthesizing the natural product hypermonone G, the amount of catalyst used is 0.05-0.15 equivalents, that is, the ratio of catalyst to raw material is 5:100-15:100.
[0020] Preferably, in the aforementioned method for synthesizing the natural product hypermonone G, the organic solvents in S1 and S2 are toluene, dichloromethane, benzene, tetrahydrofuran, chloroform, or acetonitrile; and the organic solvent in S4 is THF, diethyl ether, dichloromethane, or ethylene glycol dimethyl ether.
[0021] Preferably, in the aforementioned method for synthesizing the natural product hypermonone G, steps S1-S5 are all carried out in an inert gas environment.
[0022] Preferably, in the aforementioned method for synthesizing the natural product hypermonone G, the amount of borane dimethyl sulfide used is 2-3 equivalents; the amount of sodium hydroxide used is 2-3 equivalents; and the amount of hydrogen peroxide used is 2-3 equivalents. That is, the ratio of each component to the raw materials is 2-3:1.
[0023] Preferably, in the aforementioned method for synthesizing the natural product hypermonone G, the extraction in S3 is performed using dichloromethane, and the extraction in S5 is performed using ethyl acetate; the drying in S3 and S5 is performed using anhydrous sodium sulfate, and the concentration is performed using rotary evaporation.
[0024] The present invention also provides a product, hypermonone G, prepared according to the aforementioned method.
[0025] Beneficial effects of the present invention
[0026] 1. The natural product hypermonone G was successfully synthesized asymmetrically using the method of this invention, achieving the first artificial synthesis of the natural product hypermonone G and solving the problem that the natural product hypermonone G has not yet been artificially synthesized.
[0027] 2. The reaction process of this invention is carried out at room temperature and pressure, under mild conditions, and the process is simple and efficient. In addition, the catalyst is non-toxic and harmless, making it green and environmentally friendly.
[0028] 3. The method of the present invention is simple and easy to implement, highly practical, and has high atom economy, making it suitable for widespread promotion. Attached Figure Description
[0029] Appendix Figure 1 This is the hydrogen spectrum of hypermonone G of the present invention. Detailed Implementation
[0030] The present invention will be further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
[0031] Embodiments of the present invention
[0032] The reaction process in this embodiment of the invention is as follows: raw material 1 (3,7-dimethyloct-6-en-1-yn-3-ol) reacts under the action of a catalyst to obtain transition state 2, and then oxabicyclo[2.2.1]heptane skeleton 3 is constructed from transition state 2. Oxabicyclo[2.2.1]heptane skeleton 3 reacts in the reaction environment shown to finally form product 4 (hypermonone G).
[0033]
[0034] From the above reaction mechanism, two new chemical bonds are generated simultaneously in the key reaction of this invention. In this reaction, thanks to the coordination of the catalyst with the alkynyl group, the alkynyl group is activated. Then, the nucleophilicity of the alkene in the molecule plays a role, and the electrons on the double bond attack the activated alkynyl group to form the first carbon-carbon bond. At the same time, the newly formed tertiary carbocation is captured by the lone pair electrons on the tertiary alcohol oxygen in the molecule to form another carbon-oxygen bond, thereby constructing an oxabicyclic [2.2.1]heptane skeleton with terminal double bonds.
[0035] The key reactions of the target compound can be achieved because: firstly, the catalyst activates the alkyne group; secondly, the nucleophilicity of the alkene and the spatial proximity of the alkenyl and alkyne groups lead to a kinetically dominant five-membered ring-closing reaction; and thirdly, the intramolecular hydroxyl group can cross the ring to capture spatially close tertiary carbocations, thus enabling the efficient construction of the ring system.
[0036] Gold, as a soft transition metal, is a π-acid among Lewis acids. Its metallic properties enable it to effectively activate the triple bond of alkynyl groups. Ph3PAuCl, a commonly used gold catalyst, offers better cost-effectiveness compared to other gold catalysts and is supported by experimental evidence, demonstrating superior performance and yield.
[0037] In the borohydride oxidation reaction, the stereoselectivity of the carbon atom is controlled by the steric hindrance of the two methyl groups in the bridged ring. Due to the different steric hindrances on both sides, when the boron reagent undergoes a 2+2 cycloaddition reaction with the double bond, it can only attack from the side with smaller steric hindrance, thus generating the desired product configuration.
[0038] Example 1
[0039] A method for synthesizing the natural product hypermonone G, comprising the following steps:
[0040] S1. Under a nitrogen atmosphere, the raw material 3,7-dimethyloct-6-en-1-yn-3-ol was dissolved in toluene to obtain solution A with a concentration of 0.05M;
[0041] S2. Under a nitrogen atmosphere, triphenylphosphine chloride (0.1 eq) and silver tetrafluoroborate (0.1 eq) were dissolved in toluene to obtain solution B;
[0042] S3. Under a nitrogen atmosphere, add solution B to solution A, stir for half an hour, and monitor by TLC until the substrate reacts completely. Then quench the reaction with water, extract twice with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, concentrate by rotary evaporation, perform column chromatography on silica gel, petroleum ether:ethyl acetate (V: 10 / 1 system), and then concentrate by rotary evaporation to obtain the oxabicyclo[2.2.1]heptane skeleton;
[0043] The NMR data for the oxabicyclo[2.2.1]heptane skeleton are as follows:
[0044] 1 H NMR(400MHz,Chloroform-d)δ4.75(s,2H),2.26(d,J=3.7Hz,1H),2.02–1.90(m,1 H),1.79–1.64(m,2H),1.59–1.49(m,1H),1.33(s,3H),1.30(s,3H),1.12(s,3H).
[0045] S4. Dissolve the oxabicyclo[2.2.1]heptane skeleton in THF to obtain solution C;
[0046] S5. Add borane dimethyl sulfide (2.5 eq) solution to solution C, stir and react for 1 h. Detect complete substrate reaction by TLC. Then transfer the solution to 0 °C, add sodium hydroxide (2.5 eq) solution, react for 0.5 h, add 30% hydrogen peroxide (2.5 eq) solution, transfer to room temperature and continue reaction for 1 h. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate by rotary evaporation, perform silica gel column chromatography (petroleum ether: ethyl acetate (V: 2 / 1 system), and then concentrate by rotary evaporation to obtain the product Hypermonone G.
[0047] The NMR data for the product Hypermonone G are as follows:
[0048] 1H NMR(400MHz,Chloroform-d)δ3.95(dd,J=10.5,7.8Hz,1H),3.85(dd,J=10.5,5.6Hz,1H),2.16(d,J=3.3 Hz,1H),1.90–1.77(m,3H),1.49(ddt,J=15.5,10.6,3.3Hz,1H),1.30(s,3H),1.24(s,3H),1.16(s,3H).
[0049] Example 2
[0050] A method for synthesizing the natural product hypermonone G, comprising the following steps:
[0051] S1. Under a helium atmosphere, the raw material 3,7-dimethyloct-6-en-1-yn-3-ol was dissolved in dichloromethane to obtain solution A with a concentration of 0.05M;
[0052] S2. Under a helium atmosphere, methyltriphenylphosphine gold (0.05 eq) and phosphotungstic acid (0.05 eq) are dissolved in dichloromethane to obtain solution B;
[0053] S3. Under a helium atmosphere, add solution B to solution A, stir for half an hour, and monitor by TLC until the substrate reacts completely. Then quench the reaction with water, extract twice with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, concentrate by rotary evaporation, perform column chromatography on silica gel, petroleum ether:ethyl acetate (V: 10 / 1 system), and then concentrate by rotary evaporation to obtain the oxabicyclo[2.2.1]heptane skeleton;
[0054] S4. Dissolve the oxabicyclo[2.2.1]heptane skeleton in dichloromethane to obtain solution C;
[0055] S5. Add borane dimethyl sulfide (2 eq) solution to solution C, stir and react for 1 h. Detect complete substrate reaction using TLC. Then transfer the solution to -5℃, add sodium hydroxide (2 eq) solution, react for 40 min, add 30% hydrogen peroxide (2 eq) solution, transfer to room temperature and continue reaction for 0.5 h. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate by rotary evaporation, perform silica gel column chromatography (petroleum ether: ethyl acetate (V: 2 / 1 system), and then concentrate by rotary evaporation to obtain the product Hypermonone G.
[0056] Example 3
[0057] A method for synthesizing the natural product hypermonone G, comprising the following steps:
[0058] S1. Under a nitrogen atmosphere, the raw material 3,7-dimethyloct-6-en-1-yn-3-ol was dissolved in tetrahydrofuran to obtain solution A with a concentration of 0.05M;
[0059] S2. Under a nitrogen atmosphere, (0.15 eq) dissolved in tetrahydrofuran to obtain solution B;
[0060] S3. Under a nitrogen atmosphere, add solution B to solution A, stir for half an hour, and monitor by TLC until the substrate reacts completely. Then quench the reaction with water, extract twice with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, concentrate by rotary evaporation, perform column chromatography on silica gel, petroleum ether:ethyl acetate (V: 10 / 1 system), and then concentrate by rotary evaporation to obtain the oxabicyclo[2.2.1]heptane skeleton;
[0061] S4. Dissolve the oxabicyclo[2.2.1]heptane skeleton in ethylene glycol dimethyl ether to obtain solution C;
[0062] S5. Add borane dimethyl sulfide (3 eq) solution to solution C, stir and react for 1 h. Detect complete substrate reaction by TLC. Then transfer the solution to 5 °C, add sodium hydroxide (3 eq) solution, react for 20 min, add 30% hydrogen peroxide (3 eq) solution, and continue reacting at room temperature for 1.5 h. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate by rotary evaporation, perform silica gel column chromatography (petroleum ether: ethyl acetate (V: 2 / 1 system), and then concentrate by rotary evaporation to obtain the product Hypermonone G.
[0063] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.
Claims
1. A method for synthesizing the natural product Hypermonone G, characterized in that: Using 3,7-dimethyloct-6-en-1-yn-3-ol as a starting material, the oxabicyclo[2.2.1]heptane skeleton shown in Compound I was constructed by catalyst catalysis. Then, the oxabicyclo[2.2.1]heptane skeleton was subjected to stereoselective reaction to obtain the final product Hypermonone G. The chemical structural formula of the 3,7-dimethyloct-6-en-1-yn-3-ol is as follows: ; The chemical structural formula of compound I is as follows: ; The chemical structural formula of the product Hypermonone G is as follows: ; The catalyst is a mixture of triphenylphosphine gold chloride and silver tetrafluoroborate, a mixture of methyltriphenylphosphine gold and phosphotungstic acid, or a compound thereof. .
2. The method for synthesizing the natural product Hypermonone G according to claim 1, characterized in that, Includes the following steps: S1. Dissolve the raw material 3,7-dimethyloct-6-en-1-yn-3-ol in an organic solvent to obtain solution A; S2. Dissolve the catalyst in an organic solvent to obtain solution B; S3. Add solution B to solution A and stir until the reaction is complete. Then add water to quench the reaction. After extraction, drying, concentration, column chromatography and concentration, the oxabicyclo[2.2.1]heptane skeleton of compound I is obtained. S4. Dissolve the oxabicyclo[2.2.1]heptane skeleton in an organic solvent to obtain solution C; S5. Add borane dimethyl sulfide solution to solution C, stir until the reaction is complete, then transfer the solution to an environment of -5℃ to 5℃, add sodium hydroxide solution, react for 20-40 min, add hydrogen peroxide solution, transfer to room temperature and continue the reaction for 0.5-1.5 h, after the reaction is complete, add saturated ammonium chloride to quench the reaction, and then extract, dry, concentrate, column chromatography and concentrate in sequence to obtain the product Hypermonone G.
3. The method for synthesizing the natural product Hypermonone G according to claim 2, characterized in that: The amount of catalyst used is 0.05-0.15 equivalents.
4. The method for synthesizing the natural product Hypermonone G according to claim 2, characterized in that: The organic solvents mentioned in S1 and S2 are toluene, dichloromethane, benzene, tetrahydrofuran, chloroform, or acetonitrile; the organic solvents mentioned in S4 are THF, diethyl ether, dichloromethane, or ethylene glycol dimethyl ether.
5. The method for synthesizing the natural product Hypermonone G according to claim 2, characterized in that: All steps S1-S5 are performed in an inert gas environment.
6. The method for synthesizing the natural product Hypermonone G according to claim 2, characterized in that: The amount of borane dimethyl sulfide used is 2-3 equivalents; the amount of sodium hydroxide used is 2-3 equivalents; the amount of hydrogen peroxide used is 2-3 equivalents.
7. The method for synthesizing the natural product Hypermonone G according to claim 2, characterized in that: The extraction described in S3 is performed using dichloromethane, and the extraction described in S5 is performed using ethyl acetate; the drying described in S3 and S5 is performed using anhydrous sodium sulfate, and the concentration is performed using rotary evaporation.